The present invention relates to methods of making dihydropyrone HIV protease inhibitors.
Despite efforts to discover effective treatments or a cure, human immuno-deficiency virus (HIV) infection and the disease acquired immunodeficiency syndrome (AIDS) continue to haunt modem society. One way of combating HIV infection and AIDS has been to administer to an affected patient a compound that inhibits the viral enzyme HIV protease, which is required by the virus to reproduce. Some compounds that inhibit HIV protease are currently being marketed to treat HIV infection and AIDS and have been shown to be most effective when used in combination with other compounds that can be used to treat HIV infection and AIDS. The dihydropyrones represent a new chemical class of HIV protease inhibitors. The present invention provides a commercially viable method for making dihydropyrone HIV protease inhibitors. In particular, the present invention relates to the synthesis of (S)-6-[2-(4-Aminophenyl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one; (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one; (S)-3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one; and (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one. See, U.S. Pat. No. 5,789,440, U.S. patent application Ser. No. 08/885,743 and U.S. patent application titled xe2x80x9cHIV Protease Inhibitorsxe2x80x9d filed on the same day as the present application listing Boyer, Fred et al. as inventors, which applications and patents are hereby incorporated by reference.
The present invention provides the compounds dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester;
Dimethylthiocarbamic acid S-(2-tert-butyl-4-formyl-5-methylphenyl) ester;
Dimethylthiocarbamic acid S-(2-tert-butyl-4-hydroxymethyl-5-methylphenyl) ester;
(+/xe2x88x92)-1-Hydroxy-4-methyl-1-(4-nitrophenyl)pentan-3-one;
(+/xe2x88x92)-1-Acetoxy-4-methyl-1-(4-nitrophenyl)pentan-3-one or [Acetic acid 4-methyl-1-(4-nitro-phenyl)-3-oxo-pentyl ester].
1-(4-N-A acetylaminophenyl)-4-methylpentan-3-one or [N-[4-(4-methyl-3-oxo-pentyl)-phenyl]-acetamide].
(+/xe2x88x92)-3-[2-(4-N-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid or [3-[2-(4-acetylamino-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid].
(+/xe2x88x92)-3-Hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester or [3-hydroxy-3-isopropyl-5-(4-nitro-phenyl)-pent-4-enoic acid benzyl ester];
(+/xe2x88x92)-3-Hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester;
(+/xe2x88x92)-3-[2-(4-Aminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid;
(S)-3-[2-(4-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid;
(S)-3-[2-(4-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (S)-N-benzyl-xcex1-methylbenzylamine salt;
(S)-6-[2-(4-Acetylaminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one;
(S)-5-[2-(4-Acetylaminophenyl)ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acid ethyl ester;
(S)-N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}phenyl)acetamide;
N-(5-tert-Butyl-2-methyl-4-thiocyanatophenyl)carbamic acid tert-butyl ester; and
Toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methylphenyl) ester.
The present invention provides a method of making compounds of Formula I 
wherein
Ra and Rb are independently C1-C6 alkyl;
Rd is hydrogen, C1-C6 alkyl, or halogen;
R3 is C2-C8 cycloalkyl or C1-C6 alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, or trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the step of reacting 
wherein R4 is tolyl, phenyl, or methyl, in the presence of a tertiary amine base to give 
In a preferred embodiment of the method, the 
is further reacted with a base to form 
In another preferred embodiment, the reaction in the presence of a tertiary amine base is carried out in a low boiling point, polar, aprotic solvent.
In another preferred embodiment, the reaction in the presence of a tertiary amine base is carried out in acetonitrile or tetrahydrofuran.
In another preferred embodiment, the base is sodium hydroxide, potassium hydroxide, aqueous ammonia, or sodium methoxide.
In another preferred embodiment, the tertiary amine base is triethylamine.
In a more preferred embodiment, R3 is 
Ra is 
Rb is xe2x80x94CH3, and Rd is hydrogen.
In another more preferred embodiment, the tertiary amine base is triethylamine, and the solvent is acetonitrile.
Also provided is a method of making 
wherein
R3 is C2-C8 cycloalkyl or C1-C6 alkyl;
Rd is hydrogen, C1-C6 alkyl, or halogen; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the steps of:
a. reacting 
with carbonyl diimidazole to form 
b. reacting the 
with a compound of the formula 
and MgCl2, to form 
c. reacting the 
with a base to form 
In a preferred embodiment, the base is NaOH or KOH.
In a preferred embodiment, 
is 
and Rd is hydrogen.
Also provided is a method of resolving 
wherein
R3 is C2-C8 cycloalkyl or C1-C6 alkyl;
Rd is hydrogen, halogen, or C1-C6 alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the steps of:
a. treating 
with (S)-N-benzyl-xcex1-methyl benzyl amine;
b. allowing crystals to form;
c. collecting the crystals; and
d. isolating 
In a preferred embodiment, 
Also provided is a method of making 
wherein
R3 is C2-C8 cycloalkyl or C1-C6 alkyl;
Rd is hydrogen, halogen, or C1-C6 alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the steps of:
a. reacting 
to form 
b. reacting 
with acetic anhydride to form 
c. reacting the 
with H2 to form 
d. reacting the 
with an acylating agent to form 
e. reacting the 
with benzyl acetate or C1-C6 alkyl acetate to form 
wherein Rc is benzyl or C1-C6 alkyl;
f. reacting the 
with H2 if Rc is benzyl or aqueous base if Rc is benzyl or C1-C6 alkyl to provide 
In a preferred embodiment, the acylating agent is acetic anhydride, formic acetic anhydride, methyl formate, ethyl formate chloroformate, benzyl chloroformate, or isobutyl chloroformate, trifluoroacetic anhydride.
In another preferred embodiment, the acylating agent is acetic anhydride.
In another preferred embodiment, 
Rd is hydrogen.
Also provided is a method of making 
wherein R4 is tolyl, phenyl, or methyl, and Ra and Rb are independently C1-C6 alkyl, the method comprising the steps of:
a. reacting 
with a Lewis acid catalyst, and tri-C1-C6 alkyl orthoformate or dichloromethyl methyl ether to form 
b. reacting 
to give 
c. heating 
to produce 
d. reacting 
with a reducing agent to give 
e. heating 
with a base to give 
f. reacting the 
with a sulfonating agent R4SO2 halogen to give 
In a preferred embodiment of the method, the reducing agent is sodium borohydride or lithium borohydride.
In another preferred embodiment, the sulfonating agent R4SO2halogen is toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, or toluenesulfonylbromide.
In another preferred embodiment, the Lewis acid catalyst is AlCl3.
In another preferred embodiment, 
and Rb is xe2x80x94CH3.
Also provided is a method of making 
wherein
R3 is C2-C8 alkyl or C1-C6 alkyl,
Ra and Rb are independently C1-C6 alkyl, and Rd is hydrogen, halogen, or C1-C6 alkyl,
the method comprising the steps of:
a. reacting 
with a Lewis acid catalyst, and tri-C1-C6 alkyl orthoformate or dichloromethyl methyl ether to form 
b. reacting 
to give 
c. heating 
to produce 
d. reacting 
with a reducing agent to give 
e. heating 
with a base to give 
f. reacting the 
with a sulfonating agent R4SO2-halogen wherein R4 is tolyl, phenyl, or methyl to give 
g. reacting 
to form 
h. reacting 
with acetic anhydride to form 
i. reacting 
with a base to form 
j. reacting 
with benzyl acetate or C1-C6 alkyl acetate to form 
wherein Rc is benzyl or C1-C6 alkyl;
k. reacting 
with H2 when Rc is benzyl or aqueous base when Rc is benzyl or C1-C6 alkyl to give 
l. reacting 
with an acylating agent to form 
wherein PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl;
m. treating the 
with (S)-N-benzyl-xcex1-methyl benzylamine;
n. allowing crystals to form;
o. collecting the crystals;
p. isolating 
q. reacting 
with carbonyl diimidazole to form 
r. reacting the 
with a compound of the formula 
and MgCl2 to form 
s. reacting the 
with a base to form 
t. reacting 
in the presence of a tertiary amine base to give 
u. reacting 
with a base to form 
In a preferred embodiment, 
Rb is xe2x80x94CH3, and Rd is hydrogen.
In a preferred embodiment, in Step a the Lewis acid catalyst is AlCl3 and the tri-C1-C6 alkyl orthofornate is triethyl orthoformate. In a preferred embodiment, in Step b the 
In a preferred embodiment, in Step d the reducing agent is NaBH4.
In a preferred embodiment, in Step e the base is sodium hydroxide.
In a preferred embodiment, in Step f the sulfonating agent R4xe2x80x94SO2-halogen is 
In a preferred embodiment, in Step j the acylating agent is acetic anhydride.
In another preferred embodiment, in Step t the tertiary amine base is triethyl arnine.
In another preferred embodiment, in Step u the base is sodium hydroxide.
Also provided is a method of making 
wherein R4 is tolyl, phenyl, or methyl, and Ra and Rb are independently C1-C6 alkyl, the method comprising the steps of:
a. reacting 
with (tert-butyl OCO)2O to give 
b. reacting 
with NaSH and NaBH4 to form 
c. reacting 
with a sulfonating agent 
to give 
d. reacting 
with an acid to form 
In a preferred embodiment, the sulfonating agent 
In a preferred embodiment, wherein the acid is HCl.
Also provided is a method of making 
wherein R3 is C2-C8 cycloalkyl or C1-C6 alkyl; Ra and Rb are independently C1-C6 alkyl, Rd is hydrogen, C1-C6 alkyl or halogen, and
R2 is NH2 or xe2x80x94CH2OH, the method comprising the step of:
a. reacting 
in the presence of a base to form 
wherein R4 is tolyl, phenyl, or methyl.
In a preferred embodiment, the base is K2CO3.
In a preferred embodiment, the base is K2CO3 and the solvent is dimethylformamide.
In a preferred embodiment, 
R2 is xe2x80x94NH2, Ra is 
Rb is xe2x80x94CH3 and Rd is hydrogen.
In a preferred embodiment, 
R2 is xe2x80x94CH2OH, and Ra is 
Rb is xe2x80x94CH3 and Rd is hydrogen.
In a preferred embodiment, 
R2 is xe2x80x94CH2OH, and Ra is 
Rb is xe2x80x94CH3 and Rd is hydrogen
Also provided is a method of making 
wherein R3 is C1-C6 alkyl or C2-C8 cycloalkyl, Rd is hydrogen, halogen, or C1-C6 alkyl, the method comprising
the steps of:
a. reacting 
to form 
b. reacting 
with H2 to give 
c. reacting 
to form 
d. reacting 
with a base to form 
e. reacting 
with S-xcex1-methyl benzyl amine ;
f. allowing crystals to form;
g. collecting the crystals;
h. isolating 
i. reacting 
with carbonyl diimidazole to form 
j. reacting 
to produce 
k. reacting 
with a base to form 
l. reacting 
with H2 to form 
In a preferred embodiment, 
and Rd is hydrogen.
In a preferred embodiment, 
and Rd is hydrogen.
In a preferred embodiment, in Step d the base is potassium hydroxide.
In a preferred embodiment, in Step k the base is potassium hydroxide.
In a preferred embodiment, 
Also provided is a method of making 
wherein
R3 is C2-C8 cycloalkyl or C1-C6 alkyl;
Rd is hydrogen, halogen, or C1-C6 alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoromethyl, or isobutyl carbamoyl,
the method comprising the steps of
a. reacting 
to form 
b. reacting 
with acetic anhydride to form
c. reacting 
with a base to form 
d. reacting 
with benzyl acetate or C1-C6 alkyl acetate to form 
wherein Rc is benzyl or C1-C6 alkyl;
e. reacting 
with H2 to give 
f. reacting 
with an acylating agent to form 
Also provided is a method of making 
wherein R3 is C1-C6 alkyl or C2-C8 cycloakyl, Ra and Rb are independently C1-C6 alkyl, and Rd is hydrogen, halogen, or
C1-C6 alkyl, the method comprising the steps of:
a. reacting 
with (tert-butyl OCO)2O to give 
b. reacting 
with NaSH and NaBH4 to form 
c. reacting 
with a sulfonating agent 
to give 
wherein R4 is tolyl, phenyl, or methyl;
d. reacting 
with an acid to form 
e. reacting 
to form 
f. reacting 
with H2 to give 
g. reacting 
to form 
h. reacting 
with a base to form 
i. reacting 
with S-xcex1-methylbenzylamine;
j. allowing crystals to form;
k. collecting the crystals;
l. isolating 
m. reacting 
with carbonyl diimidazole to form 
n. reacting 
to produce 
o. reacting 
with a base to form 
p. reacting 
with H2 to form 
q. reacting 
with 
in the presence of a base to form 
In a preferred embodiment, 
Rb is xe2x80x94CH3, and Rd is hydrogen.
In another preferred embodiment, the sulfonating agent 
In another preferred embodiment, the acid is HCl.
In another preferred embodiment, in Step h in base is sodium hydroxide.
In another preferred embodiment, in Step o the base is potassium hydroxide.
Also provided are the compounds (+/xe2x88x92)-3-[2-(4-Acetylamino-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid benzyl ester;
(S)-N-{4-[3-Hydroxy-3-(2-imidazol-1-yl-2-oxo-ethyl)-4-methyl-pentyl]-phenyl}-acetamide;
(S)-3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-1-imidazol-1-yl-4-methyl-pentan-1-one;
4-Methyl-1-(4-nitro-phenyl)-pent-1-en-3-one;
(S)-5-(3-Benzyloxy-phenyl)-3-cyclopentyl-3-hydroxy-1-imidazol-1-yl-pentan-1-one;
(+/xe2x88x92)-3-[2-(4-N-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid; and
(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acid tert-butyl ester.
The present invention relates to methods of making dihydropyrone HIV protease inhibitors. The methods involve a coupling reaction of two intermediates to form the product HIV protease inhibitor. This coupling reaction can be used with various intermediates to form HIV protease inhibitors.
The specific syntheses disclosed herein are intended to exemplify certain embodiments of the invention, and are not intended to limit the scope of the specification or claims in any matter.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon having from 1 to 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, octyl, and the like.
The term xe2x80x9cacylating agentxe2x80x9d means a chemical reagent that reacts with a compound to add an acyl group 
to the compound. An acyl group is an organic radical derived from an organic acid by the removal of the hydroxyl group. Representative examples of acylating agents include, but are not limited to acetic anhydride, formic acetic anhydride, methyl formate, ethyl chloroformate, benzyl chloroformate, and isobutyl chloroformate.
The term xe2x80x9cLewis acid catalystxe2x80x9d means a Lewis acid that is used as a catalyst for a chemical reaction. A Lewis acid is an electron pair acceptor. Examples of Lewis acid catalysts include, but are not limited to, AlCl3, AlBr3, ZnCl2, BF3, and TiCl4.
The term xe2x80x9chalogenxe2x80x9d means chlorine, fluorine, bromine, or iodine.
The term xe2x80x9creducing agentxe2x80x9d means a chemical reagent that is readily oxidized by reducing another chemical. Examples of reducing agents include, but are not limited to, hydrogen, LiAlH4, and NaBH4.
The term xe2x80x9cbasexe2x80x9d means a chemical reagent that yields a hydroxyl ion in aqueous solution and which reacts with an acid to form water and a salt. Another definition of a base is a chemical reagent that is an electron donor. Examples of bases include, but are not limited to, potassium hydroxide, sodium hydroxide, NaHCO3, Na2CO3 K2CO3, KHCO3, pyridine, and triethylamine.
The term xe2x80x9cacidxe2x80x9d means a chemical reagent that yields a proton (H+) in aqueous solution and which reacts with a base or metals to form water and a salt. Another definition of an acid is a chemical reagent that is an electron pair acceptor. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydriodic acid, and acetic acid.
The term xe2x80x9csulfonating agentxe2x80x9d means a chemical reagent that can substitute a hydrogen atom on a compound with a xe2x80x94SO3H group or xe2x80x94SO3R group. Examples of sulfonating agents include, but are not limited to, 
The term xe2x80x9cprotecting groupxe2x80x9d is an organic group that has converted a reactive functional group on a compound into an unreactive functional group so that a reaction can be run on the compound without the reactive functional group interfering with the reaction. Examples of reactive functional groups that can be protected include, but are not limited to, alcohols, aldehydes, ketones, carboxylic acids (xe2x80x94CO2H), and amines. The protecting group used depends on the functional group to be protected. For example, amines can be protected by acetyl groups.
A comprehensive guide to protecting groups can be found in Greene T. W., xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John Wiley and Sons, Inc, New York, 1981, which is hereby incorporated by reference.
The following abbreviations are used throughout this application.
